rs17636067

Variant names:

• chr8-18057617-C-T
• rs17636067
• NM_177924.5:c.1105G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_177924.5(ASAH1):​c.1105G>A​(p.Val369Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,598,538 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V369A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (45 hom.)
• Consequence: ASAH1 NM_177924.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.09
• Publications: 12 publications found

Genes affected

ASAH1 (HGNC:735): (N-acylsphingosine amidohydrolase 1) This gene encodes a member of the acid ceramidase family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. Processing of this preproprotein generates alpha and beta subunits that heterodimerize to form the mature lysosomal enzyme, which catalyzes the degradation of ceramide into sphingosine and free fatty acid. This enzyme is overexpressed in multiple human cancers and may play a role in cancer progression. Mutations in this gene are associated with the lysosomal storage disorder, Farber lipogranulomatosis, and a neuromuscular disorder, spinal muscular atrophy with progressive myoclonic epilepsy. [provided by RefSeq, Oct 2015]

ASAH1 Gene-Disease associations (from GenCC):

• ASAH1-related sphingolipidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Farber lipogranulomatosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• spinal muscular atrophy-progressive myoclonic epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_177924.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0107887685).
• BP6: Variant 8-18057617-C-T is Benign according to our data. Variant chr8-18057617-C-T is described in ClinVar as Benign. ClinVar VariationId is 362373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00407 (619/152246) while in subpopulation EAS AF = 0.0232 (120/5182). AF 95% confidence interval is 0.021. There are 5 homozygotes in GnomAd4. There are 337 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177924.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	NM_177924.5	MANE Select	c.1105G>A	p.Val369Ile	missense	Exon 14 of 14	NP_808592.2	Q13510-1
	ASAH1	NM_004315.6		c.1153G>A	p.Val385Ile	missense	Exon 14 of 14	NP_004306.3
	ASAH1	NM_001127505.3		c.1087G>A	p.Val363Ile	missense	Exon 14 of 14	NP_001120977.1	Q13510-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.1105G>A	p.Val369Ile	missense	Exon 14 of 14	ENSP00000490272.1	Q13510-1
	ASAH1	ENST00000381733.9	TSL:1	c.1153G>A	p.Val385Ile	missense	Exon 14 of 14	ENSP00000371152.4	Q13510-2
	ASAH1	ENST00000314146.10	TSL:1	c.1087G>A	p.Val363Ile	missense	Exon 14 of 14	ENSP00000326970.10	Q13510-3

Frequencies

GnomAD3 genomes AF: 0.00405 AC: 616 AN: 152130 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0229

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0229

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00877 AC: 2200 AN: 250950 AF XY: 0.00709

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.0376

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.0330

Gnomad FIN exome AF: 0.00347

Gnomad NFE exome AF: 0.000846

Gnomad OTH exome AF: 0.00718

GnomAD4 exome AF: 0.00238 AC: 3447 AN: 1446292 Hom.: 45 Cov.: 30 AF XY: 0.00215 AC XY: 1545 AN XY: 719872

African (AFR) AF: 0.000755 AC: 25 AN: 33092

American (AMR) AF: 0.0374 AC: 1653 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.00306 AC: 78 AN: 25474

East Asian (EAS) AF: 0.0223 AC: 862 AN: 38626

South Asian (SAS) AF: 0.000895 AC: 77 AN: 86010

European-Finnish (FIN) AF: 0.00457 AC: 237 AN: 51910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.000285 AC: 314 AN: 1101922

Other (OTH) AF: 0.00339 AC: 201 AN: 59356

GnomAD4 genome AF: 0.00407 AC: 619 AN: 152246 Hom.: 5 Cov.: 32 AF XY: 0.00453 AC XY: 337 AN XY: 74434

African (AFR) AF: 0.00164 AC: 68 AN: 41536

American (AMR) AF: 0.0230 AC: 351 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.0232 AC: 120 AN: 5182

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.00283 AC: 30 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68026

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00261 Hom.: 20

Bravo AF: 0.00608

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00719 AC: 873

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	ASAH1-related disorders (1)
-	-	1	Farber lipogranulomatosis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.1
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.24
Sift	Benign	0.064	T
Sift4G	Benign	0.17	T
Polyphen		0.92	P
Vest4		0.052
MVP		0.79
MPC		0.0036
ClinPred		0.011	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.75
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17636067; hg19: chr8-17915126;